The presence of essential metals (trace elements) in sufficient quantities and in a biologically available form in diet is essential for maintaining the health and well-being of domestic animals and poultry. Because essential metals such as copper, iron, manganese and zinc are often deficient in common feed ingredients, supplemental amounts of these nutrients are often added to the feed of domesticated animals and poultry. Many commercial feed additives have been developed to provide the essential metals in forms that are readily biologically utilizable. The degree of biological availability of nutrients is often referred to as “bioavailability”. Bioavailability of essential metals depends on the physical and/or chemical properties of the form in which the metal is present in the diet. Increased bioavailability of supplemental metals is beneficial because it allows the use of lower concentrations of the metals in the diet to meet the nutritional needs of animals, while lowering the potential harmful effects of high levels of these metals both on the animals and on the environment.
Several commercial products are available in which trace elements are more bioavailable than the corresponding inorganic source of the metal. The enhanced bioavailability is attributed to the association of the metal with an organic molecule, generally known as ligand. This association or bonding results in the increased availability of the metal for utilization by animals, i.e. increased bioavailability. The increased bioavailability of the essential elements in these products is the result of increased solubility, greater stability in the gut, enhanced absorption into circulation and/or improved metabolic utilization.
Different types of products that contain a trace element associated with an organic ligand are commercially available. These can be classified in different groups based on the nature of the ligand used in manufacturing the product. In one class of products, amino acids are used as the ligands that form complexes or chelates with the metal. Examples of these products are described in U.S. Pat. Nos. 3,941,818; 3,950,372; 4,067,994; 4,863,898 4,900,561; 4,948,594; 4,956,188; 5,061,815; 5,278,329; 5,583,243; and 6,166,071. A second group of feed additives include the metal salts of short chain carboxylic acids such as propionic acid (See U.S. Pat. Nos. 5,591,878, 5,707,679, 5,795,615 and 5,846,581). A third group of trace element additives is classified by the American Feed Control Officials as Metal Proteinate and defined as “the product resulting from the chelation of a soluble salt with amino acids and/or partially hydrolyzed protein”. Examples of these products are described in U.S. Pat. Nos. 3,440,054, 3,463,858, 3,775,132, 3,969,540, 4,020,158, 4,076,803, 4,103,003, 4,172,072 and 5,698,724
The assignee of the present application has in the past synthesized and patented metal complexes of amino acids as a more bioavailable source of the essential elements. The following are examples of these patents: U.S. Pat. Nos. 3,941,818; 3,950,372; 4,021,569; 4,039,681; and 4,067,994 disclose 1:1 complexes of alpha amino acids, preferably DL-methionine with the transition metals zinc, chromium, manganese and iron. The formation of similar complexes with L-methionine is disclosed in U.S. Pat. No. 5,278,329. U.S. Pat. Nos. 4,900,561 and 4,948,594 disclose copper complexes of alpha amino acids containing terminal amino groups. Complexes of copper, manganese, zinc and iron with alpha hydroxyl aliphatic carboxylic acids are disclosed in U.S. Pat. Nos. 4,956,188 and 5,583,243. U.S. Pat. Nos. 4,670,269 and 4,678,854 disclose complexes of cobalt with poly-hydroxyl carboxylic acid such as glucoheptanoic acid. Complexes of the amino acid L-lysine with trace elements are disclosed in U.S. Pat. No. 5,061,815. The effectiveness of the compounds disclosed in these patents has been demonstrated from data provided in some of these patents and in numerous scientific publications and technical reports.
The above patents describe the use of pure synthetic or natural amino or hydroxyl acids. In U.S. Pat. No. 5,698,724 the assignee of the current application disclosed the synthesis of complexes of essential elements with natural amino acids obtained by the hydrolysis of proteins. Since this patent was issued, a large number of field studies have demonstrated that metals from these complexes are more bioavailable than metals from inorganic sources.
Based on Zinpro Corporation's experience with metal-amino acid complexes as described in the references cited above, we have concluded that the 1:1 complexes of the metals Zn, Mn, Cu, Co, Fe are effective nutritional sources of the metals and more advantageous than the 1:2 complexes. These 1:1 complexes exist as ion pairs in which the metal-amino acid comprises the cation. The counter ion (anion) is provided by a mineral acid and is necessary for balancing the charge on the cation. The requirement for the external anion results in products in which the metal content is limited.
The invention of U.S. Pat. No. 7,129,375 was to develop metal amino acid complexes in which the amino acid serves a dual role. It serves as the bidentate ligand to form a complex with the metal ion, and it serves as the counter ion to balance the charge on the cationic complex. One of the acids used in that invention was glutamic acid. While these types of complexes are useful as animal feed supplements, they suffer from difficulties during the drying process.
Lysine is an essential amino acid in the diet of mammals. That is, lysine cannot be synthesized by mammals at a rate adequate to meet metabolic requirements and so must be supplied in the diet. Corn (Zea mays L.) is notoriously low in lysine and, if used in a single grain ration, requires lysine supplementation to maintain animal health and for economical animal growth. The present invention, by forming metal lysine complexes, supplements both trace metals and the essential amino acid lysine by the addition of a single dietary supplement. It is believed that the metal component of the metal lysine complex is more easily transported through the intestinal wall with the lysine component than when in the form of an ionic salt. Lesser amounts of the metals, accordingly, may be added to the diet to effect adequate supplementation.
In another commonly owned U.S. Pat. No. 5,061,815, the amino acid lysine (Lys) is complexed with a metal ion (M), where M is iron (Fe++ or Fe+++), copper (Cu++), zinc (Zn++), manganese (Mn++) or cobalt (CO++) by reaction in an aqueous solution under acidic conditions of a lysine containing compound and a salt of the metal. These complexes are either a 1:1 metal to lysine ([Lys]M) complexes or a 2:1 lysine to metal ([Lys]2 M) complex. These complexes, when administered parenterally or as a dietary supplement in animals or as a foliar spray in plants, provide a readily assimilated source of the metals for use in the metabolic processes of the organism.
It can be seen from the above description that organic trace minerals have a wide acceptance for the benefits in animal nutrition. There are many patents related to their structures, use and manufacturing. There are also many different types of ligands used in their production. Each of these metal complexes discussed has advantages and disadvantages. One of the more common ligands that have been around for a number of years are the amino acids. For amino acids only four are commercially available at a reasonable cost to produce organic trace minerals. Those four are methionine, glutamic acid, glycine and lysine. Lysine and glutamic acid are particularly desirable because of ease of solubility and readily available sources at reasonable cost. The lysine and glutamic acid combination also are from two different classes of amino acids (cationic and anionic). Each of these metal amino acid complexes has advantages and disadvantages. This patent seeks to eliminate the disadvantages while retaining all the advantages.
Accordingly, it is a primary objective of the present invention to prepare reasonable cost, highly soluble mixed amino acid ligands of lysine and glutamic acid with metals for animal nutrition, particularly trace elements iron, manganese, copper and zinc. One advantage of the mixed amino acid salt is that it combines a pendant acid and a pendant base that form a salt to ensure solubility.
Another important objective of the present invention is to provide additional supplements for animals/poultry that contain mixed amino acid complexes that take advantage of use of two different amino acid transport pathways for providing bioavailability of both the amino acid and the associated trace element, metal.
The method and means of accomplishing these as well as other objectives of the invention will become apparent from the description which follows.